A novel series of putative Brugia malayi histone demethylase inhibitors as potential anti-filarial drugs.
Filariasis, caused by a family of parasitic nematodes, affects millions of individuals throughout the tropics and is a major cause of acute and chronic morbidity. Current drugs are largely used in mass drug administration programs aimed at controlling the spread of disease by killing microfilariae,...
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ftdoajarticles:oai:doaj.org/article:db2089a885cb4872bfd7f10fac7334c0 2023-05-15T15:09:37+02:00 A novel series of putative Brugia malayi histone demethylase inhibitors as potential anti-filarial drugs. Tamara Kreiss Tyler Eck Brittany Hart Sreedhar Tummalapalli David Rotella John Siekierka 2022-03-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0010216 https://doaj.org/article/db2089a885cb4872bfd7f10fac7334c0 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0010216 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0010216 https://doaj.org/article/db2089a885cb4872bfd7f10fac7334c0 PLoS Neglected Tropical Diseases, Vol 16, Iss 3, p e0010216 (2022) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2022 ftdoajarticles https://doi.org/10.1371/journal.pntd.0010216 2022-12-31T03:31:05Z Filariasis, caused by a family of parasitic nematodes, affects millions of individuals throughout the tropics and is a major cause of acute and chronic morbidity. Current drugs are largely used in mass drug administration programs aimed at controlling the spread of disease by killing microfilariae, larval forms of the parasite responsible for transmission from humans to humans through insect vectors with limited efficacy against adult parasites. Although these drugs are effective, in some cases there are toxic liabilities. In case of loiasis which is caused by the parasitic eyeworm Loa loa, mass drug administration is contraindicative due to severe side effects of microfilariae killing, which can be life threatening. Our screening program and medicinal chemistry efforts have led to the identification of a novel series of compounds with potent killing activity against adult filarial parasites and minimal activity against microfilariae. A structural comparison search of our compounds demonstrated a close structural similarity to a recently described histone demethylase inhibitor, GSKJ1/4 which also exhibits selective adult parasite killing. We demonstrated a modification of histone methylation in Brugia malayi parasites treated with our compounds which might indicate that the mode of drug action is at the level of histone methylation. Our results indicate that targeting B. malayi and other filarial parasite demethylases may offer a novel approach for the development of a new class of macrofilaricidal therapeutics. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 16 3 e0010216 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Tamara Kreiss Tyler Eck Brittany Hart Sreedhar Tummalapalli David Rotella John Siekierka A novel series of putative Brugia malayi histone demethylase inhibitors as potential anti-filarial drugs. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Filariasis, caused by a family of parasitic nematodes, affects millions of individuals throughout the tropics and is a major cause of acute and chronic morbidity. Current drugs are largely used in mass drug administration programs aimed at controlling the spread of disease by killing microfilariae, larval forms of the parasite responsible for transmission from humans to humans through insect vectors with limited efficacy against adult parasites. Although these drugs are effective, in some cases there are toxic liabilities. In case of loiasis which is caused by the parasitic eyeworm Loa loa, mass drug administration is contraindicative due to severe side effects of microfilariae killing, which can be life threatening. Our screening program and medicinal chemistry efforts have led to the identification of a novel series of compounds with potent killing activity against adult filarial parasites and minimal activity against microfilariae. A structural comparison search of our compounds demonstrated a close structural similarity to a recently described histone demethylase inhibitor, GSKJ1/4 which also exhibits selective adult parasite killing. We demonstrated a modification of histone methylation in Brugia malayi parasites treated with our compounds which might indicate that the mode of drug action is at the level of histone methylation. Our results indicate that targeting B. malayi and other filarial parasite demethylases may offer a novel approach for the development of a new class of macrofilaricidal therapeutics. |
format |
Article in Journal/Newspaper |
author |
Tamara Kreiss Tyler Eck Brittany Hart Sreedhar Tummalapalli David Rotella John Siekierka |
author_facet |
Tamara Kreiss Tyler Eck Brittany Hart Sreedhar Tummalapalli David Rotella John Siekierka |
author_sort |
Tamara Kreiss |
title |
A novel series of putative Brugia malayi histone demethylase inhibitors as potential anti-filarial drugs. |
title_short |
A novel series of putative Brugia malayi histone demethylase inhibitors as potential anti-filarial drugs. |
title_full |
A novel series of putative Brugia malayi histone demethylase inhibitors as potential anti-filarial drugs. |
title_fullStr |
A novel series of putative Brugia malayi histone demethylase inhibitors as potential anti-filarial drugs. |
title_full_unstemmed |
A novel series of putative Brugia malayi histone demethylase inhibitors as potential anti-filarial drugs. |
title_sort |
novel series of putative brugia malayi histone demethylase inhibitors as potential anti-filarial drugs. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2022 |
url |
https://doi.org/10.1371/journal.pntd.0010216 https://doaj.org/article/db2089a885cb4872bfd7f10fac7334c0 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 16, Iss 3, p e0010216 (2022) |
op_relation |
https://doi.org/10.1371/journal.pntd.0010216 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0010216 https://doaj.org/article/db2089a885cb4872bfd7f10fac7334c0 |
op_doi |
https://doi.org/10.1371/journal.pntd.0010216 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
16 |
container_issue |
3 |
container_start_page |
e0010216 |
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1766340776787181568 |